In neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, neurons may die by a form of programmed cell death called apoptosis. A major effort in the Cellular and Molecular Neurosciences section of the Laboratory of Neurosciences is aimed at establishing what triggers apoptosis in neurodegenerative disorders and how neuronal degeneration might be prevented by targeting specific molecular events in the process of apoptosis. We have found that a protein called p53 is involved in the death of neurons in experimental models of Alzheimer's, Parkinson's and Huntington's diseases. Novel specific inhibitors of p53 were developed and several lead agents were shown to be effective in animal models of stroke and Parkinson's disease. In other studies we established important roles for potassium ion fluxes in the pathogenesis of neuronal degeneration in models of stroke. A drug called diazoxide that opens mitochondrial potassium channels was neuronprotective in models of stroke. In studies of the mechanism by which neurons die in Alzheimer's disease we have found that damage to DNA causes the neurons to undergo an abortive attempt to re-enter the cell cycle resulting in activation of the ATM kinase and p53 which trigger apoptosis. Our studies of telomere function in neurons have revealed roles for several telomere-associated proteins in preventing apoptosis. Damage to mitochondrial DNA may also trigger apoptosis, but a DNA repair protein called OGG1 can protect neurons from dying in models of neurodegenerative disorders. In addition, we have identified a mitochondrial uncoupling protein (UCP4) that can protect neurons in models relevant to stroke and Alzheimer's disease by a mechanism involving suppression of oxidative stress and stabilization of cellular calcium homeostasis. We have also established roles for brain-derived neurotrophic factor (BDNF) in preventing the apoptosis of neurons produced from stem cells in the hippocampus, a finding that suggests the possibility of increasing the capacity of the brain to replace lost and damaged neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000313-05
Application #
7132238
Study Section
(LNS)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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